Acquisition of simple auditory and visual sequences in cerebellar patients

Previous studies suggest a role of the cerebellum in detecting and recognizing event sequences. In the present study sequences of two acoustic tones of different frequencies and sequences of two visual stimuli with different colours were presented with short, long and very long durations. Thirteen cerebellar patients and 13 controls were required to indicate whether the order of stimuli was identical or opposite to a reference by saying 'yes' or 'no'. To minimize motor requirements no time restrictions were given. In none of the test conditions a significant difference between patients and controls was observed. The results suggest that the cerebellum is not essential for acquisition of simple sensory sequences. Differences in findings between previous and the present study may be explained by differences in motor demands and the explicit nature of the tasks.     

Predictive Motor Timing Performance Dissociates Between Early Diseases of the Cerebellum and Parkinson's Disease

There is evidence that both the basal ganglia and the cerebellum play a role in the neural representation of time in a variety of behaviours, but whether one of them is more important is not yet clear. To address this question in the context of predictive motor timing, we tested patients with various movement disorders implicating these two structures in a motor-timing task. Specifically, we investigated four different groups: (1) patients with early Parkinson's disease (PD); (2) patients with sporadic spinocerebellar ataxia (SCA); (3) patients with familial essential tremor (ET); and (4) matched healthy controls. We used a predictive motor-timing task that involved mediated interception of a moving target, and we assessed the effect of movement type (acceleration, deceleration and constant), speed (slow, medium and fast) and angle (0°, 15° and 30°) on performance (hit, early error and late error). The main results showed that PD group and arm ET subgroup did not significantly differ from the control group. SCA and head ET subjects (severe and mild cerebellar damage, respectively) were significantly worse at interception than the other two groups. Our findings support the idea that the basal ganglia play a less significant role in predictive motor timing than the cerebellum. The fact that SCA and ET subjects seemed to have a fundamental problem with predictive motor timing suggests that the cerebellum plays an essential role in integrating incoming visual information with the motor output in a timely manner, and that ET is a heterogeneous entity that deserves increased attention from clinicians.     

Visual search disorders beyond pure sensory failure in patients with acute homonymous visual field defects

Patients with homonymous visual field defects (HVFD) are often crucially disabled during self-guided visual exploration of their natural environment. Abnormal visual search may be related to the sensory deficit, deficient spatial orientation or compensatory eye movements. We tested the hypothesis that visual search in HVFD is purely determined by the visual–sensory deficit by comparing nine patients with HVFD due to occipital stroke in an acute stage to nine healthy subjects with technically simulated “virtual” homonymous visual field defects (vHVFD) and to nine controls with normal visual fields. The simulated gaze-contingent visual field defects in vHVFD subjects were individually matched to the patients’ HVFD with respect to their size and side. Eye movements were recorded while subjects searched for targets among distractors and indicated target detection by clicks.All patients, in particular those with lesions involving the inferior occipito-temporal (fusiform) gyrus, but also those with small lesions restricted to the visual cortex, showed longer search durations than vHVFD subjects. This was tightly related to the higher number of fixations and particularly “re-fixations” (repeated scanning of fixated items). Working memory across saccades during the search was intact (no increased “re-clicks”). Scanpath strategies were similar in patients and vHVFD subjects. For both groups amplitude and frequency of saccades did not differ between the hemifields.In HVFD patients with acute occipital brain lesions, visual input failure does not fully account for abnormal visual search. It might either result from disconnections of the primary visual cortex to associated occipital and temporal brain areas or reflect an early stage of compensatory eye movements which differ from chronic HVFD patients.     

Cerebellar involvement in motor but not sensory adaptation

Predictable sensorimotor perturbations can lead to cerebellum-dependent adaptation--i.e., recalibration of the relationship between sensory input and motor output. Here we asked if the cerebellum is also needed to recalibrate the relationship between two sensory modalities, vision and proprioception. We studied how people with and without cerebellar damage use visual and proprioceptive signals to estimate their hand's position when the sensory estimates disagree. Theoretically, the brain may resolve the discrepancy by recalibrating the relationship between estimates (sensory realignment). Alternatively, the misalignment may be dealt with by relying less on one sensory estimate and more on the other (a weighting strategy). To address this question, we studied subjects with cerebellar damage and healthy controls as they performed a series of tasks. The first was a prism adaptation task that involves motor adaptation to compensate for a visual perturbation and is known to require the cerebellum. As expected, people with cerebellar damage were impaired relative to controls. The same subjects then performed two experiments in which they reached to visual and proprioceptive targets while a visuoproprioceptive misalignment was gradually imposed. Surprisingly, cerebellar patients performed as well as controls when the task invoked only sensory realignment, but were impaired relative to controls when motor adaptation was also possible. Additionally, individuals with cerebellar damage were able to use a weighting strategy similarly to controls. These results demonstrate that, unlike motor adaptation, sensory realignment and weighting are not cerebellum-dependent.     

Visual scanning and matching dysfunction in brain-damaged patients with drawing impairment.

Visual matching and visual exploration were examined in 7 normal subjects and 20 brain-damaged patients with drawing impairment measured by the Bender Gestalt Visual-Motor Test. Right brain-damaged patients made significantly more errors of rotation and integration than left brain-damaged patients. Selecteded Bender figures were also used as stimuli for both visual matching and visual exploration tests. The ability to match Bender figures was found to be impaired in right but not left brain-damaged patients. All patients showed eye movement and fixation patterns different from those normals. Patients essentially had more fixations and shorter fixation durations. Significant intercorrelations were found between the total Bender Gestalt score and visual matching and visual exploration scores. These findings indicate that visual matching and visual exploration measures can be used to evaluate perceptual impairment in individuals who do not have adequate motor responses or where impaired motor responses may confound interpretations about visual cognitive impairment.     

A study of arm movements in Huntington's disease under visually controlled and blindfolded conditions

The so-called bradykinesia of Huntington's disease (HD) seems not due to reduced movement speed alone but may also be task-dependent. We therefore investigated the influence of visual control on the ability of HD patients to perform a motor task. Ten HD patients, never treated with neuroleptic drugs and with mild functional impairment in activities of daily living, performed the task blindfolded and not blindfolded, as did 10 age- and education-matched healthy controls. The task was to use the dominant hand to trace out the contours of a 20×20 cm square in a clockwise direction, pausing at each corner. The square was marked on the table at which the subject sat. Accuracy was stressed rather than speed. A videocamerabased system recorded movement trajectories, from which kinematic and error parameters were derived. Patients and controls moved at comparable speeds but patients took longer to complete the task due to more curvilinear and hence longer trajectories.Patients spent more time in the deceleration phase of the movement, and in the blindfold condition had more variable movements as indicated by greater error variability scores. Correlation analysis showed that kinematic parameters in patients did not correlate with involuntary movement scores. These findings indicate that abnormalities of motor control are present in HD when movement accuracy (and not velocity) is required. HD patients are more dependent on visual control than normal subjects. Received: 9 September 2002 / Accepted in revised form: 18 October 2002 Correspondence to F. Carella     

Cortical excitability in juvenile myoclonic epileptic patients and their asymptomatic siblings: A transcranial magnetic stimulation study

In this study, we aimed to evaluate motor cortical excitability changes in patients with juvenile myoclonic epilepsy (JME) and their asymptomatic siblings (AS) using single-pulse transcranial magnetic stimulation (spTMS). 21 patients with JME and their 21 AS were compared to 20 healthy controls. All of JME patients were receiving antiepileptic therapy and their seizures were well controlled. Firstly, standard EEG examinations and then TMS studies were performed. Resting motor threshold (RMT), motor evoked potential (MEP) amplitudes, the durations of central motor conduction time (CMCT) and cortical silent period (CSP) were measured. After TMS studies, EEG recordings were repeated in an hour to evaluate any effect of TMS study on EEG. There were no significant differences between the first and second EEG recordings. No seizures were recorded during and after the TMS study. RMT was found higher in JME patients than AS and normal controls. There were no significant differences between cortical MEP amplitudes and MEP amplitude/CMAP (compound muscle action potential) amplitude ratio in all three groups. CMCT duration was shorter in JME patients than AS. CSP durations of JME patients were found to be longer than controls. In AS, CSP durations were also found to be longer than controls but this difference was not found statistically significant. Our results suggested that although high MT may be related to antiepileptic therapy, the prolongation of CSP duration may reflect impairment of supraspinal and/or intracortical inhibitory mechanism in JME. To eliminate the drug effect, further studies are needed in newly diagnosed JME patients without medication and large series of their asymptomatic siblings.     

Visual search deficits in Williams-Beuren syndrome

Williams-Beuren syndrome (WBS) is a rare genetic condition characterized by several physical and mental traits, such as a poor visuo-spatial processing and a relative strength in language. In this study we investigated how WBS subjects search and scan their visual environment. We presented 10 search displays on a computer screen to WBS subjects as well as control subjects, with the instruction to find a target out of several stimulus elements. We analyzed the eye movement patterns for fixation characteristics and systematicy of search. Fixations generally lasted longer in WBS subjects than in control subjects. WBS subjects made more fixations at a stimulus element they had already looked at and more fixations that were not aimed at a stimulus element at all, decreasing the efficiency of search. These outcomes lead to the conclusion that visual search of individuals with Williams-Beuren syndrome is less effective than in control subjects. This finding may be related to their motor deficits, an impaired processing of global visual information and/or deficits in working memory and could reflect impairments within the dorsal stream.     

The vestibulo-ocular reflex as a model system for motor learning: what is the role of the cerebellum?

Motor systems are under a continuous adaptive process to maintain behavior throughout developmental changes and disease, a process called motor learning. Simple behaviors with easily measurable inputs and outputs are best suited to understand the neuronal signals that contribute to the required motor learning. Considering simple behaviors, the vestibulo-ocular reflex (VOR) allows quantification of its input and motor output and its neural circuitry is among the best documented. The main candidates for plastic change are the cerebellum and its target neurons in the brainstem. This review focuses on recent data regarding the involvement of the cerebellum in VOR motor learning. Learning can be divided into that acutely acquired over a period of hours and that chronically acquired over longer periods. Both acute and chronic learning have three phases named acquisition, consolidation, and retention. The cerebellar role in retention is disputed, but there is a consensus on the need of an intact cerebellum for acquisition. Data from neuronal recording, lesion studies and transgenic mouse experiments is complex but suggests that the signal representation in the cerebellum contains aspects of both motor output and sensory input. The cerebellum apparently uses different mechanisms for acute and chronic learning as well as for increases and decreases in VOR gain. Recent studies also suggest that the signal content in the cerebellum changes following learning and that the mechanisms used for chronic adaptation involve not only changes in a head velocity component but also in the efference copy of an eye movement command signal reaching Purkinje cells. This data leads to a new conceptual framework having implications for developing theories on the role of the cerebellum in motor learning and in the search for plastic elements within the VOR circuitry. For chronic learning we hypothesize that changes in the head velocity information traveling through the circuitry occur in parallel with changes in the integrator pathway and the efference copy pathway. We further propose that these changes are necessary to maintain the broadband characteristics of the learned behavior.     

Impaired motor learning and diffuse axonal damage in motor and visual systems of the rat following traumatic brain injury

Cognitive-motor functioning or motor skill learning is impaired in humans following traumatic brain injury. A more complete understanding of the mechanisms involved in disorders of motor skill learning is essential for any effective rehabilitation. The specific goals of this study were to examine motor learning disorders, and their relationship to pathological changes in adult rats with mild to moderate closed head injury. Motor learning deficits were determined by comparing the ability to complete a series of complex motor learning tasks with simple motor activity. The extent of neuronal damage was determined using silver impregnation. At all post-injury time points (day 1 to day 14), statistically significant deficits were observed in parallel bar traversing, foot placing, ladder climbing, and rope climbing. Performance improved with time, but never reached control levels. In contrast, no deficits were found in simple motor activity skills tested with beam balance and runway traverse. Histologically, axonal degeneration was widely distributed in several brain areas that relate to motor learning, including the white matter of sensorimotor cortex, corpus callosum, striatum, thalamus and cerebellum. Additionally, severely damaged axons were observed in the primary visual pathway, including the optic chiasm, optic tract, lateral geniculate nuclei, and superior colliculus. These findings suggest that motor learning deficits could be detected in mild or moderate brain injury, and this deficit could be attributed to a diffuse axonal injury distributed both in the motor and the visual systems.     

Typical visual search performance and atypical gaze behaviors in response to faces in Williams syndrome

Background

Evidence indicates that individuals with Williams syndrome (WS) exhibit atypical attentional characteristics when viewing faces. However, the dynamics of visual attention captured by faces remain unclear, especially when explicit attentional forces are present. To clarify this, we introduced a visual search paradigm and assessed how the relative strength of visual attention captured by a face and explicit attentional control changes as search progresses.

Methods

Participants (WS and controls) searched for a target (butterfly) within an array of distractors, which sometimes contained an upright face. We analyzed reaction time and location of the first fixation—which reflect the attentional profile at the initial stage—and fixation durations. These features represent aspects of attention at later stages of visual search. The strength of visual attention captured by faces and explicit attentional control (toward the butterfly) was characterized by the frequency of first fixations on a face or butterfly and on the duration of face or butterfly fixations.

Results

Although reaction time was longer in all groups when faces were present, and visual attention was not dominated by faces in any group during the initial stages of the search, when faces were present, attention to faces dominated in the WS group during the later search stages. Furthermore, for the WS group, reaction time correlated with eye-movement measures at different stages of searching such that longer reaction times were associated with longer face-fixations, specifically at the initial stage of searching. Moreover, longer reaction times were associated with longer face-fixations at the later stages of searching, while shorter reaction times were associated with longer butterfly fixations.

Conclusions

The relative strength of attention captured by faces in people with WS is not observed at the initial stage of searching but becomes dominant as the search progresses. Furthermore, although behavioral responses are associated with some aspects of eye movements, they are not as sensitive as eye-movement measurements themselves at detecting atypical attentional characteristics in people with WS.

     

The Basis of Visual Constructional Disability in Patients with Unilateral Cerebral Lesions

Patients with left and right unilateral hemispheric lesions were compared on the Form Assembly Task, a visual construction task requiring perceptual but not executive, motor, or verbal skills. Right lesioned patients were inferior to lefts and normals in both degree and frequency of impairment. Performances on the assembly task and two visual discrimination tasks were correlated among right but not left lesioned patients. Left lesioned patients took significantly longer to achieve maximum level of performance than either rights or normals. Neither sex nor duration of lesion affected Form Assembly performance. Results were consistent with the hypothesis that visual perceptual deficits underlie constructional difficulties among right but not left lesioned patients.     

Visual information processing after severe closed head injury: effects of forward and backward masking.

Three tachistoscopic tasks were employed to assess whether survivors of severe closed head injury (CHI) exhibit a disturbance of information processing within peripheral and/or central visual pathways. Twelve survivors of severe CHI and 12 individually matched control subjects completed a recognition threshold (no mask) task, a monoptic, forward masking by visual noise task (to assess processing within relatively peripheral pathways), and a dichoptic, backward masking by pattern task (to assess processing within central pathways). For each experimental procedure, the minimum exposure durations required by subjects to identify correctly single consonants and triple consonants were determined. Survivors of severe CHI showed deficits on all three visual tasks. Both groups also had higher threshold durations for the more complex stimuli (triple v single consonants), but differences in threshold were greater in the patients with CHI. The degree of perceptual impairment exhibited by patients with CHI was highly variable and not consistently related to injury characteristics or residual motor or speech and language impairment.     

Visual search and eye movements in patients with chronic solvent-induced toxic encephalopathy

Various aspects of visual perception have been found to be impaired in patients with occupational chronic solvent-induced toxic encephalopathy (CSE). The purpose of the study was to characterise the changes in eye movements and visual search performance in CSE patients. We measured eye movements of 13 CSE patients and 22 healthy controls during dynamic visual search task by using a fast video eye tracker. The task was to search for and identify a target letter among numerals presented in a rectangular stimulus matrix (3 × 3–10 × 10 items). Threshold search time, i.e. the duration of stimulus presentation required for identifying the target with a given probability was determined by using a psychophysical staircase method. The visual search times of the CSE patients were clearly longer, and they needed considerably more eye fixations than healthy controls to find the target. Thus, their reduced performance in this task was mainly related to the reduction in the number of items which could be processed during a single eye fixation (perceptual span). This reduction probably reflects a limited capacity of visual attention, since visual acuity, contrast sensitivity, and the oculomotor saccade velocity were found to be normal. The results suggest that motor slowness or low-level visual factors do not explain the poor performance of CSE patients in visual search tasks. The results are also discussed with respect to the effects of education, and compared to the performance in the widely used neuropsychological Trail Making Test, which uses similar stimuli and requires visual search.     

Response to sensory uncertainty in Parkinson’s disease: a marker of cerebellar dysfunction?

Motor performance is profoundly influenced by sensory information, yet sensory input can be noisy and uncertain. The basal ganglia and the cerebellum are important in processing sensory uncertainty, as the basal ganglia incorporate the uncertainty of predictive reward cues to reinforce motor programs, and the cerebellum and its connections mitigate the effect of ambiguous sensory input on motor performance through the use of forward models. Although Parkinson's disease (PD) is classically considered a primary disease of the basal ganglia, alterations in cerebellar activation are also observed, which may have consequences for the processing of sensory uncertainty. The aim of this study was to investigate the effect of visual uncertainty on motor performance in 15 PD patients and ten age-matched control subjects. Subjects performed a visually guided tracking task, requiring large-amplitude arm movements, by tracking with their index finger a moving target along a smooth trajectory. To induce visual uncertainty, the target position randomly jittered about the desired trajectory with increasing amplitudes. Tracking error was related to target ambiguity to a significantly greater degree in PD subjects off medication compared with control subjects, indicative of susceptibility to visual uncertainty in PD. l-Dopa partially ameliorated this deficit. We interpret our findings as suggesting an inability of PD subjects to create adequate forward models and/or de-weight less informative visual input. As these computations are normally associated with the cerebellum and connections, we suggest that alterations in normal cerebellar functioning may be a significant contributor to altered motor performance in PD.     

Long-term follow-up of patients with type 2 and non-ambulant type 3 spinal muscular atrophy (SMA) treated with olesoxime in the OLEOS trial

In a previous Phase 2 study, olesoxime had a favorable safety profile. Although the primary endpoint was not met, analyses suggested that olesoxime might help in the maintenance of motor function in patients with Types 2/3 SMA. This open-label extension study (OLEOS) further characterizes the safety, tolerability and efficacy of olesoxime over longer therapy durations. In OLEOS, no new safety risks were identified. Compared to matched natural history data, patients treated with olesoxime demonstrated small, non-significant changes in motor function over 52 weeks. Motor function scores were stable for 52 weeks but declined over the remainder of the study. The greatest decline in motor function was seen in patients ≤15 years old, and those with Type 2 SMA had faster motor function decline versus those with Type 3 SMA. Previous treatment with olesoxime in the Phase 2 study was not protective of motor function in OLEOS. Respiratory outcomes were stable in patients with Type 3 SMA >15 years old but declined in patients with Type 2 SMA and in patients with Type 3 SMA ≤15 years old. Overall, with no stabilization of functional measures observed over 130 weeks, OLEOS did not support significant benefit of olesoxime in patients with SMA.     

Cerebellar contributions to reach adaptation and learning sensory consequences of action

When we use a novel tool, the motor commands may not produce the expected outcome. In healthy individuals, with practice the brain learns to alter the motor commands. This change depends critically on the cerebellum as damage to this structure impairs adaptation. However, it is unclear precisely what the cerebellum contributes to the process of adaptation in human motor learning. Is the cerebellum crucial for learning to associate motor commands with novel sensory consequences, called forward model, or is the cerebellum important for learning to associate sensory goals with novel motor commands, called inverse model? Here, we compared performance of cerebellar patients and healthy controls in a reaching task with a gradual perturbation schedule. This schedule allowed both groups to adapt their motor commands. Following training, we measured two kinds of behavior: in one case, people were presented with reach targets near the direction in which they had trained. The resulting generalization patterns of patients and controls were similar, suggesting comparable inverse models. In the second case, participants reached without a target and reported the location of their hand. In controls, the pattern of change in reported hand location was consistent with simulation results of a forward model that had learned to associate motor commands with new sensory consequences. In patients, this change was significantly smaller. Therefore, in our sample of patients, we observed that while adaptation of motor commands can take place despite cerebellar damage, cerebellar integrity appears critical for learning to predict visual sensory consequences of motor commands.     

Visual exploration of non-verbal material by dyslexic children

Eye movements were recorded from fifteen matched pairs of dyslexic children and normal readers (boys) during a field of search task. The task required the subjects to locate a target that matched a central standard. The relative familiarity of elements in the array, the array density, and the tilt of the elements with respect to the central standard were varied. Results showed that the dyslexic children took significantly longer than controls to find the matching target when the elements in the array were tilted, and somewhat (though not significantly) longer when the material was unfamiliar. Within the dyslexic group, search durations were related to graphomotor skills and to WRAT reading level. Two explanations for the results were proposed: (1) dyslexic children may have a specific difficulty in processing directionally confusing information; (2) some dyslexic children may have a pervasive difficulty in motoric gating of visual information.     

A loss of a velocity‐duration trade‐off impairs movement precision in patients with cerebellar degeneration

Current theories discussing the role of the cerebellum have been consistently pointing towards the concept of motor learning. The unavailability of a structure for motor learning able to use information on past errors to change future movements should cause consistent metrical deviations and an inability to correct them; however, it should not boost “motor noise.” However, dysmetria, a loss of endpoint precision and an increase in endpoint variability (“motor noise”) of goal‐directed movements is the central aspect of cerebellar ataxia. Does the prevention of dysmetria or “motor noise” by the healthy cerebellum tell us anything about its normal function? We hypothesize that the healthy cerebellum is able to prevent dysmetria by adjusting movement duration such as to compensate changes in movement velocity. To address this question, we studied fast goal‐directed index finger movements in patients with global cerebellar degeneration and in healthy subjects. We demonstrate that healthy subjects are able to maintain endpoint precision despite continuous fluctuations in movement velocity because they are able to adjust the overall movement duration in a fully compensatory manner (“velocity‐duration trade‐off”). We furthermore provide evidence that this velocity‐duration trade‐off accommodated by the healthy cerebellum is based on a priori information on the future movement velocity. This ability is lost in cerebellar disease. We suggest that the dysmetria observed in cerebellar patients is a direct consequence of the loss of a cerebellum‐based velocity‐duration trade‐off mechanism that continuously fine‐tunes movement durations using information on the expected velocity of the upcoming movement.     

Visual hemispatial inattention: stimulus parameters and exploratory strategies.

Patients with unilateral hemispheric lesions were given visual target cancellation tasks. As expected, marked contralateral and less severe ipsilateral visual inattention were observed in patients with right-sided cerebral lesions whereas those with left-sided lesions showed only mild contralateral neglect. Stimulus material (shapes vs letters) and array (random vs structured) interacted in a complex manner to influence target detection only in patients with right-sided lesions. Furthermore, the search strategy of these patients tended to be erratic, particularly when the stimuli were in an unstructured array. A structured array prompted a more systematic and efficient search. It appears, therefore, that stimulus content and spatial array affect neglect behaviour in patients with right-sided lesions and that a lack of systematic visual exploration within the extrapersonal space is one factor that contributes to visual hemispatial inattention.